Chapter 14 : Oxidative Phosphorylation as a Target Space for Tuberculosis: Success, Caution, and Future Directions

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The genus comprises a group of obligately aerobic bacteria that have adapted to inhabit a wide range of intracellular and extracellular environments. Fundamental to this adaptation is the ability to respire and generate energy from variable sources and to sustain metabolism in the absence of growth. The pioneering work of Brodie and colleagues on established much of the primary information on the electron transport chain and oxidative phosphorylation system in mycobacteria (reviewed in ). Mycobacteria can only generate sufficient energy for growth by coupling the oxidation of electron donors derived from organic carbon catabolism (e.g., NADH, succinate, malate) to the reduction of O as a terminal electron acceptor. Mycobacterial genome sequencing revealed that branched pathways exist in mycobacterial species for electron transfer from many low-potential reductants, via quinol, to oxygen ( Fig. 1 ).

Citation: Cook G, Hards K, Dunn E, Heikal A, Nakatani Y, Greening C, Crick D, Fontes F, Pethe K, Hasenoehrl E, Berney M. 2017. Oxidative Phosphorylation as a Target Space for Tuberculosis: Success, Caution, and Future Directions, p 295-316. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0014-2016
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Figure 1

Generalized schematic overview of relevant electron transfer components of . Complexes indicated in blue oxidize various substrates to reduce quinones. The resulting (mena)quinol molecules (orange) can be oxidized to result in reduction of various terminal electron acceptors, mediated by the complexes shown in purple.

Citation: Cook G, Hards K, Dunn E, Heikal A, Nakatani Y, Greening C, Crick D, Fontes F, Pethe K, Hasenoehrl E, Berney M. 2017. Oxidative Phosphorylation as a Target Space for Tuberculosis: Success, Caution, and Future Directions, p 295-316. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0014-2016
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Figure 2

Mechanisms by which a proton motive (membrane potential [Δψ] + transmembrane pH gradient [ZΔpH]) force can be generated in mycobacteria. Cotransport of protons driven by solute (succinate) symport into the periplasm. Redox-loop separation of charge; (mena)quinol oxidation results in proton release into the periplasm by virtue of (mena)quinol site proximity to the periplasm, while electrons are transferred to reduce a terminal electron acceptor (e.g., nitrate, fumarate) in the cytoplasm that results in neutralization of charge. Proton translocation mediated by primary proton-pumping complexes ( - supercomplex).

Citation: Cook G, Hards K, Dunn E, Heikal A, Nakatani Y, Greening C, Crick D, Fontes F, Pethe K, Hasenoehrl E, Berney M. 2017. Oxidative Phosphorylation as a Target Space for Tuberculosis: Success, Caution, and Future Directions, p 295-316. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0014-2016
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Figure 3

Traditional inhibitors of proton motive force generation. Valinomycin is an ionophore, selective for potassium ions, which equilibrates the potassium gradient—dissipating the Δψ (electrogenic). Nigericin is a hydrophobic weak carboxylic acid which can traverse the membrane as its either protonated acid or neutral salt. It dissipates chemical gradients (i.e., ΔpH) but maintains the charge (one positive charge exchanged for one positive charge—electroneutral) ( ). Carbonyl cyanide m-chlorophenyl hydrazine (CCCP) is an electrogenic protonophore. CCCP is driven to the periplasm by the Δψ, while CCCPH is driven to the cytoplasm by the ΔpH. It can equilibrate both Δψ and ΔpH. Model for uncoupling by either pyrazinamide (PZA) or BDQ. (Left side) PZA diffuses into the cell and is converted to pyrazinoic acid (POA) by PncA (pyrazinamidase). Anionic POA could effectively inhibit growth through anion accumulation in the neutral pH of the cytoplasm and/or efflux from the cells to become protonated in the acidic extracellular environment (POA-H). POA-H would then diffuse back into the cell driven by the ΔpH gradient and dissociate in the cytoplasm (neutral pH), leading to intracellular acidification and cell death. (Right side) In a typical mycobacterial cell, the majority of ATP synthesis is respiratory, driven by the PMF. The binding of BDQ to the c-ring most likely perturbs the a-c subunit interface, causing an uncontrolled proton leak uncoupled from ATP synthesis and resulting in a futile proton cycle. Compensation by the exchange of other cations (i.e., K) would allow the process to remain electroneutral.

Citation: Cook G, Hards K, Dunn E, Heikal A, Nakatani Y, Greening C, Crick D, Fontes F, Pethe K, Hasenoehrl E, Berney M. 2017. Oxidative Phosphorylation as a Target Space for Tuberculosis: Success, Caution, and Future Directions, p 295-316. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0014-2016
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Figure 4

Inhibitors of the electron transport chain and FF-ATP synthase of . Selected inhibitors of these complexes are indicated with flathead arrows and do not reflect the binding site of the inhibitors. Abbreviations: QPs, quinolinyl pyrimidines; TPZ, trifluoperazine; CFZ, clofazimine; 3-NP, 3-nitropropionate; SQ109, -adamantan-2-yl--(()-3,7-dimethyl-octa-2,6-dienyl)-ethane-1,2-diamine; LPZ, lansoprazole; Q203, imidazopyridine amide; BDQ, bedaquiline.

Citation: Cook G, Hards K, Dunn E, Heikal A, Nakatani Y, Greening C, Crick D, Fontes F, Pethe K, Hasenoehrl E, Berney M. 2017. Oxidative Phosphorylation as a Target Space for Tuberculosis: Success, Caution, and Future Directions, p 295-316. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0014-2016
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Figure 5

Proposed menaquinone biosynthesis pathway in mycobacteria based on the known pathway in . In this scheme the product of MenA is depicted as the quinone rather than the quinol. This is consistent with the majority of the menaquinone literature ( ), which indicates that the oxidation from quinol to quinone is spontaneous but differs from ubiquinone synthesis. The arrows indicate C2 and C3 of menaquinone-9(II-H). Abbreviations: DHNA, 1,4-dihydroxy-2-naphthoate; DHNA-CoA, 1,4-dihydroxy-2-naphthoyl-CoA; OSB, -succinylbenzoate; OSB-CoA, -succinylbenzoyl-CoA; SEPHCHC, 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexadiene-1-carboxylate; SHCHC, 2-succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylate.

Citation: Cook G, Hards K, Dunn E, Heikal A, Nakatani Y, Greening C, Crick D, Fontes F, Pethe K, Hasenoehrl E, Berney M. 2017. Oxidative Phosphorylation as a Target Space for Tuberculosis: Success, Caution, and Future Directions, p 295-316. In Jacobs, Jr. W, McShane H, Mizrahi V, Orme I (ed), Tuberculosis and the Tubercle Bacillus, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.TBTB2-0014-2016
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